Elucigene FH20 and LIPOchip are genetic tests used to diagnose familial hypercholesterolemia. A cost-utility analysis found that while these tests on their own were not cost-effective, a strategy using comprehensive genetic analysis for index cases and targeted genetic testing for relatives was the most accurate and cost-effective approach. There is uncertainty around test sensitivities due to limited evidence and a changing testing environment.

1. Elucigene FH20 and LIPOchip
for the diagnosis of for the
Elucigene and LIPOchip familial
hypercholesterolemia
diagnosis of familial
hypercholesterolemia.1,2,
Sharma P1, Boyers D1,2, Boachie C
Stewart F2, Miedzybrodzka Z, Simpson W,
The National Institute for health and Clinical
Kilonzo M, McNamee P, Mowatt G.
Excellence (NICE): Diagnostic Assessment Review
Presented (DAR)
by: Dwayne Boyers
9th HTAi Annual Meeting
26th June, 2012, Bilbao
Sharma P, Boyers D, Boachie C, Stewart F, Miedzybrodzka Z,
Simpson W, Kilonzo M, McNamee P, Mowatt G
1 Health Services Research Unit (HSRU); 2 Health Economics Research Unit
(HERU),
University of Aberdeen, Aberdeen, Scotland, U.K.

2. Familial
Hypercholesterolemia (FH)
• an autosomal dominant genetic condition
– Heterozygous / Homozygous
– 3 Culprit genes (LDLR / PSCK9 / APOB)
• Increased risk of coronary heart disease
• Prevalence estimated at 1/500 in the UK
– approx 100,000 people in the UK have FH
– Approx 85% of these remain undiagnosed

3. Tests considered
• Elucigene FH20 (Tepnel Diagnostics)
• LIPOchip v.10 (Progenika)
– (i) Test processed at UK genetics lab
– (ii) Test conducted by manufacturer in Spain – if
negative on LIPOchip, full LDLR sequencing
• Comprehensive Genetic Analysis (CGA)
– Indirectly recommended by NICE CG71
• LDL_C testing
– Current standard of care

4. Strategies modelled
Test for Index case Test for Relative
Elucigene Targeted genetic test
LIPOchip (UK lab based test) Targeted genetic test
LIPOchip (sample sent to Spain) Targeted genetic test
Elucigene - MLPA Targeted genetic test
Elucigene - LIPOchip Targeted genetic test
Elucigene – LIPOchip - MLPA Targeted genetic test
Elucigene – LIPOchip - CGA Targeted genetic test
Elucigene - CGA Targeted genetic test
LIPOchip - MLPA Targeted genetic test
LIPOchip - CGA Targeted genetic test
CGA Targeted genetic test
LDL-C only LDL-C

5. Diagnostic accuracy:
Elucigene FH20
Study Country Diagnosis Criteria Total, n Sensitivity Specificity
% %
Hooper 2009 Australia DFH Dutch 63 28.6 NC
Taylor 2010 England DFH Simon Broome 190 48.6 NC
Taylor 2010 England PFH Simon Broome 394 40.2 NC
Taylor 2010 England UFH Simon Broome 51 38.5 NC
Taylor 2010 England DFH/PFH/UFH Simon Broome 635 44.0 NC
Yarram 2010 England DFH/PFH/UFH Simon Broome 104 52.0 NC

6. Diagnostic accuracy:
LIPOchip v.10
Study id LIPOchip Diagnosis Criteria Total Sensitivity Specificity
version n % %
Palacios V 10 NR Simon Broome 126 78.5 NC
UK mutations
Callaway 2010 V 8 DFH or possible Simon Broome 22 33.3 93.8
(251 mutations)
Palacios 2010 V8 NR Simon Broome 120 56.9 NC
(251 mutations)
Stef 2009 247 mutations NR Dutch MedPed 2,462 94.5 NC
Alonso 2009 195 mutations DFH, probable Dutch criteria 808 78.0 NC
FH

7. Diagnostic accuracy:
LDL-C for index cases
Study ID Criteria Diagnosis Total, n Sensitivity % Specificity %
Damgaard 2005 Simon Broome Overall 408 90 29
Dutch 408 99 6
MedPed 408 54 83
Civeira 2008 Simon Broome Overall 825 93 28
Dutch Overall 825 88 18
MedPed Overall 825 91 53
Widhalm 2003 MedPed Adults 147 66 NC
Children 116 81 NC
Mabuchi 2005 LDLC> 4mmol/L 281 98 NC

8. Diagnostic accuracy:
LDL-C for relatives
Study ID Country Participants Total, n Sensitivity Specificity
% %
Lee 2010 UK Relatives 90 91.5 93.0
45-54years old group 80.0 70.0
Starr 2008 Netherlands First-degree relatives 3294 68.0 85.2
Denmark First-degree relatives 321 79.4 85.1
Norway First-degree relatives 1116 83.7 83.8
Wiegman Netherlands Children of definite FH 611 96.0 NC
2003 parents

9. Diagnostic accuracy:
Discussion
• Specificity of genetic tests assumed equal to 1
• Sensitivity of CGA assumed equal to 1 (Caveat?)
– All cases will also receive LDL-C testing
• Uncertainty in estimates of sensitivity across studies
– Limited evidence on most recent versions of tests
– Fast changing environment - analysis at a snapshot in
time
– LIPOchip – is MLPA required aswell?

10. Cost-effectiveness
• Cost-utility analysis (cost per QALY)
– Cohort of 1000 index cases with suspected FH
– Cascade testing of at risk 1st, 2nd and 3rd degree
relatives
• Time horizon: Patient life time
• Discounting: Costs and QALYs (3.5%)
• Perspective: UK NHS

11. Methods
• Model informed by sensitivity and prevalence rates
• Costs
– Diagnostics (MOLUs)
– Clinical management
– Drug treatment
– Reduced cardiovascular events
• QALYs
– QALY gains from reduced mortality, reduced
cardiovascular events

12. Cost-effectiveness
results
Total Total Incremental Incremental ICER
Test strategy Costs QALYs costs (£) QALYS (£/QALY)
Elucigene £43,371,985 36,653
LDL-C £43,880,789 34,744 Dominated Dominated Dominated
Elucigene_MLPA £44,470,770 37,216 Ext. Dom Ext. Dom Ext. Dom
LIPOchip £46,506,304 38,240 Ext. Dom Ext. Dom Ext. Dom
Elucigene_Lipochip £46,578,004 38,240 Dominated Dominated Dominated
LIPOchip processed in Spain £47,298,810 38,668 £3,926,825 2,015 £1,949
LIPOchip_MLPA £47,597,529 38,803 Ext. Dom Ext. Dom Ext. Dom
Elucigene_LIPOchip_MLPA £47,669,229 38,803 Dominated Dominated Dominated
CGA £48,501,362 39,231 £1,202,552 563 £2,135
Elucigene_CGA £48,548,912 39,231 Dominated Dominated Dominated
LIPOchip_CGA £48,672,212 39,231 Dominated Dominated Dominated
Elucigene_Lipochip_CGA £48,743,912 39,231 Dominated Dominated Dominated

13. Cost-effectiveness
acceptability curves

14. Discussion:
Cost-effectiveness
• Little high quality evidence of test accuracy
• Rapidly evolving environment:
– Tests constantly improving
– New versions of tests being developed
– Next generation sequencing
• Results and conclusions were robust a range of
sensitivity analyses

15. Conclusions
• Uncertainty surrounding true sensitivity of tests
• Elucigene and LIPOchip are not cost-effective as
standalone tests for the detection of FH among index
cases or for the identification of at risk relatives for
cascade testing
• A strategy of CGA for index cases and targeted
sequencing for relatives was deemed the approach with
greatest diagnostic accuracy and was therefore the most
cost-effective strategy
– Only at very high sensitivity (>70%) would Elucigene be a
cost-effective pre-screen to CGA
• LIPOchip is unlikely to be cost-effective given concerns
over the detection of deletions and duplications compared
with MLPA

16. Thank you very much
Contact Details:
d.boyers@abdn.ac.uk
Useful links:
http://www.abdn.ac.uk/heru
http://www.abdn.ac.uk/hsru
http://www.nice.org.uk
http://www.hta.co.uk
This project was funded by the National Institute for Health Research Health Technology
Assessment (NIHR HTA) programme and commissioned on behalf of NICE. It will be published
in full in the Health Technology Assessment journal series. Visit the HTA programme website for
more details www.hta.ac.uk/project/2450. The views and opinions expressed therein are those
of the authors and do not necessarily reflect those of the HTA programme, NICE, NIHR, NHS or
the Department of Health.’